Synthetic approaches to physiologically active polycyclic compounds: III. Ritter reaction with ketones of the adamantane and oxahomoadamantane series

Article abstract of DOI:10.1023/B:RUJO.0000036069.44467.04

Some previously unknown acetamino derivatives were synthesized by the Ritter reaction from ketones of the adamantane and oxahomoadamantane series. The presence of a hydroxy group as substituent in adamantan-2-one gives rise to formation of acetamino derivatives as products of replacement of the hydroxy group and transformation of the carbonyl group.

Full text of DOI:10.1023/B:RUJO.0000036069.44467.04

Russian Journal of Organic Chemistry, Vol. 40, No. 4, 2004, pp. 497–501. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 4, 2004,
pp. 528–532.
Original Russian Text Copyright © 2004 by Averina, Borisova, Zefirova, Selyunina, Zyk, Zefirov.
Synthetic Approaches to Physiologically Active
Polycyclic Compounds: III.* Ritter Reaction with Ketones
of the Adamantane and Oxahomoadamantane Series
N. V. Averina, G. S. Borisova, O. N. Zefirova, E. V. Selyunina,
N. V. Zyk, and N. S. Zefirov
Faculty of Chemistry, Lomonosov Moscow State University, Leninskie gory, Moscow, 119992 Russia
Received June 15, 2003
Abstract—Some previously unknown acetamino derivatives were synthesized by the Ritter reaction from
ketones of the adamantane and oxahomoadamantane series. The presence of a hydroxy group as substituent in
adamantan-2-one gives rise to formation of acetamino derivatives as products of replacement of the hydroxy
group and transformation of the carbonyl group.
adamantanone by the Ritter reaction. We examined the
Ritter reaction with lactone Ib, adamantan-2-one, and
5-hydroxyadamantan-2-one (III).
Computer simulation showed that some ada-
mantane and bicyclo[3.3.1]nonane derivatives could
bind to protein molecules which are targets for taxane
antitumor agents. We have initiated studies on the
development of synthetic methods for modification of
functional groups in the above cage-like compounds
with the goal of introducing thereto fragments of
taxane derivatives, which are responsible for binding
to proteins [1–4].
The reaction of lactone Ib with acetonitrile in the
system trifluoroacetic acid–BF3·Et2O gave compound
IIb as the only product (Scheme 1). In the mass
spectrum of IIb we observed the molecular ion peak
with m/z 207, and its elemental composition and the
1
13
IR and H and C NMR spectra were consistent with
the assumed structure. Gas chromatographic–mass
spectrometric analysis of the reaction mixture showed
the presence of a small amount (<5%) of an isomer
differing by orientation of the acetamino group on C4.
We previously [4] examined the possibility for
synthesizing model compounds having substituents in
positions 3, 5, and 7 of the bicyclo[3.3.1]nonane
skeleton, one of which is 5-acetamino group. We pro-
posed specific conditions for the Ritter reaction with
1-hydroxy-4-oxahomoadamantan-5-one (Ia) (heating
with acetonitrile in trifluoroacetic acid in the presence
of boron trifluoride–ether complex), which resulted in
formation of compound Ic via replacement of the
hydroxy group at the bridgehead position of the oxa-
homoadamantane system by acetamino group [4, 5].
Although oxahomoadamantanone (Ib) and its deriva-
tives usually undergo cleavage–cyclization reactions
(Scheme 1) leading to 2,4-disubstituted adamantanes
[6, 7], we detected no compound IIa in the Ritter
reaction with lactone Ia [4].
The reaction mixture obtained by the Ritter reaction
with 5-hydroxyadamantan-2-one (III) in trifluoroacetic
Scheme 1.
Nu
O
H+
C
O
O
R
R
Ia–Ic
MeCN, BF3 ·Et2O
MeCONH
O
Insofar as the yield of 1-acetamino-5-oxahomo-
adamantan-4-one (Ic) was fairly low, the present study
was aimed at synthesizing acetamino derivatives of
R
IIa, IIb
* For communications I and II, see [1, 2].
R = OH (a), H (b), NHCOMe (c).
1070-4280/04/4004-0497 © 2004 MAIK “Nauka/Interperiodica”

AVERINA et al.
498
acid in the presence of boron trifluoride–ether complex
(Scheme 2) contained three products with Rf 0.52,
0.41, and 0.1 (TLC on Alufol plates with chloroform as
eluent). These products were separated by column
chromatography on aluminum oxide using the same
eluent. The fraction with Rf 0.52 was additionally
purified by column chromatography on Al2O3 using
CH2Cl2–acetone (4:1) as eluent. In the IR spectrum
of the product with Rf 0.41 we observed absorption
bands assignable to amide (1645 cm–1), free C=O
(1725 cm–1), and NH groups (3290 cm–1). The mass
spectrum contained the molecular ion peak with
m/z 207. These data allowed us to identify the product
with Rf 0.41 as N-(4-oxoadamantan-1-yl)acetamide
the adamantane ring protons) belong to two acetyl
groups. In the 13C NMR spectrum we observed signals
from two carbon atoms attached to nitrogen. Using the
APT pulse sequence, we found that the signals at
δC 52.69 and 53.28 ppm (intensity ratio 4:1) belong to
C4 of two isomers and that the signal at δC 50.40 ppm
arises from the C1 carbon atom linked to nitrogen.
These data, in combination with the proton signal
1
intensities in the H NMR spectrum, indicate that bis-
(acetamino) derivative V was obtained as a mixture of
two stereoisomers. The mass spectrum of V contained
the molecular ion peak, m/z 250, and fragment ion
peaks with the following m/z values: 235 (M+ – CH3),
207 (M+ – CH3CO), 191 (M+ – NHCOCH3), 176
(191 – CH3), 148 (191 – CH3CO), 132 (191 –
CH3CONH2). The fragmentation pattern is consistent
with the presence in molecule V of two acetamino
groups, one of which is attached to a tertiary carbon
atom, and the other, to CH.
1
(IV). Its structure was also confirmed by the H NMR
spectrum and elemental analysis.
Scheme 2.
O
O
The observed transformation of carbonyl group into
acetamino was surprising, for there are no published
data on such reactions. Taking into account that no
analogous acetamino derivatives were formed from
5-hydroxyadamantan-2-one and adamantan-2-one
under standard conditions of the Ritter reaction [4], we
examined the reaction of unsubstituted adamantanone
with acetonitrile in trifluoroacetic acid in the presence
of boron trifluoride–ether complex, which was ex-
pected to afford compound IV. However, the IR
spectrum of the product contained a broad absorption
band only from amide carbonyl group (1645 cm–1) and
NH group (3300 cm–1). In the 1H NMR spectrum, apart
from the NH proton signal and those belonging to
the adamantane ring, a multiplet at δ 4.05 ppm was
present, which was identical to the NCH signal in the
spectrum of V. The 13C NMR spectrum, where only
the amide carbonyl carbon signal was observed, com-
pletely coincided with the spectrum of compound VIa
[8]. The above data indicate that the Ritter reaction
with adamantan-2-one gives compound VIa, in which
MeCN, BF3 ·Et2O
HO
MeCONH
III
IV
5
NHCOMe
4
6
9
+
+
IIb (isomer mixture)
7
3
10
1
2
8
NHCOMe
V
According to the analytical data, the product with
Rf 0.52 (yield 10%) had the formula C12H17NO2, but its
melting point (119–120°C) and mass spectrum
considerably differed from those found for compound
IV. GC–MS analysis and NMR data showed that this
product is most likely to be a mixture of stereo- and
structural isomers of compound IIb with a molecular
weight of 207.
The IR spectrum of the product with Rf 0.1 con-
tained a broad absorption band from amide carbonyl
(1650 cm–1) and NH group (3300 cm–1), while no
ketone carbonyl absorption was observed. In the
1H NMR spectrum of this compound, broadened
singlets at δ 5.68 and 5.29 ppm were present. These
signals were assigned to protons of two NH groups.
Therefore, we presumed that the product has struc-
ture V having two acetamino groups. The signal at
δ 4.05 ppm corresponds to the NCH proton in position
4, and two narrow singlets at δ 1.93 and 2.01 ppm
(which are partially obscured by multiplet signals from
Scheme 3.
NHCOR
O
RCN
BF3 ·Et2O
VIa, VIb
IV
R = Me (a), Ph (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 4 2004

SYNTHETIC APPROACHES TO PHYSIOLOGICALLY ACTIVE ... III.
499
Scheme 4.
Me
C
O
C
a
b
Ph
Ph
CH
Ph
Me
C
O
C
H+
MeCN
PhCOMe
Ph
CH2
Ph
Me
C
O
NHCOMe
CH2
C
Ph
VII
OH
Me
Ph CH NH
O
C
Me
the acetamino group occupies position 2 of the ada-
mantane skeleton (Scheme 3).
II and IV can be used in the synthesis of trisubstituted
bicyclo[3.3.1]nonanes which are potential antitumor
agents.
The transformation of carbonyl group into acet-
amino in the system trifluoroacetic acid–BF3·Et2O was
also observed in the reaction of adamantan-2-one with
benzonitrile. The major product was compound VIb,
and benzamide was also formed as by-product. Pre-
sumably, the reaction involves intermediate formation
of trifluoroacetoxy derivatives which are capable of
readily eliminating trifluoroacetyl group thus favoring
generation of adamantyl cation with the positive
charge centered at position 2 [9–11].
EXPERIMENTAL
1
The H and 13C NMR spectra were recorded on
a Varian VXR-400 instrument (400 MHz for 1H) using
tetramethylsilane as internal reference. The IR spectra
were recorded on a UR-20 spectrometer from samples
dispersed in mineral oil. The progress of reactions was
monitored by thin-layer chromatography on Silufol
UV-254 and Alufol plates. Silicagel L 40/100 µm and
Al2O3 (Brockman activity grade II) were used for
column chromatography.
It should be emphasized that the formation of
acylamino derivatives V, VIa, and VIb is not the result
of somewhat unusual Ritter reaction conditions. For
example, acetophenone reacts with acetonitrile under
standard conditions (with H2SO4 as catalyst) to afford
N-(1-methyl-4-oxo-2,4-diphenylbutyl)acetamide (VII)
(the reaction follows pathway a or b [12] in
Scheme 4). The same product was obtained by us from
acetophenone and acetonitrile in trifluoroacetic acid
in the presence of boron trifluoride–ether complex.
Although the melting point of our product VII slightly
differed from that reported in [12], its elemental com-
position and spectral parameters were consistent with
the assumed structure.
N-(4-Oxoadamantan-2-yl)acetamide (IIb). Oxa-
homoadamantanone Ib, 0.7 g (3.7 mmol), was dis-
solved in 5 ml of acetonitrile, 2 ml of boron tri-
fluoride–ether complex in 5 ml of trifluoroacetic acid
was added, and the mixture was stirred for 3 h on
heating (after 1 h, the mixture turned dark red). The
mixture was evaporated by half, treated with a sa-
turated solution of NaHCO3, and extracted with
chloroform, and the extract was dried over Na2SO4.
The extract contained intial lactone (Rf 0.7) and
a product with Rf 0.38 (Silufol, benzene–ethyl acetate,
2 : 1). The products were separated by column
chromatography on silica gel to isolate 0.13 g of initial
lactone Ib and 0.44 g of compound IIb as colorless
crystals. Yield of IIb 60%, mp 165–170°C. IR spec-
trum, ν, cm–1: 3310 (NH), 1725 (C=O), 1645 (C=O,
Our results showed that acetamino-substituted ada-
mantanones can be prepared by the Ritter reaction in
trifluoroacetic acid, catalyzed by boron trifluoride–
ether complex, from both unsubstituted oxahomoada-
mantanone and adamantanone having a hydroxy group
in the bridgehead position. However, in the latter case,
replacement of the hydroxy group by acetylamino is
accompanied by reductive substitution at the ketone
carbonyl. Analogous products, 2-aminoadamantanes,
can readily be obtained under similar conditions from
unsubstituted adamantan-2-one. Acetamino derivatives
1
amide). H NMR spectrum (CDCl3), δ, ppm: 5.92 br.s
(1H, NH), 4.48 m (1H, NCH), 2.56 d (1H, 3-H), 1.8–
2.25 m (14H, adamantane), 1.90 s (CH3). 13C NMR
spectrum (CDCl3), δC, ppm: 217.7, 169.8 (C=O); 58.5
(CN); 52.3 (2C); 47.0, 39.5, 39.3, 36.0, 34.0 (ada-
mantane); 24.3 (CH3). Mass spectrum: 207 [M]+, 179,
164, 148, 137. Found, %: C 69.97; H 8.69; N 6.61.
C12H17NO2. Calculated, %: C 69.54; H 8.27; N 6.76.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 40 No. 4 2004

AVERINA et al.
500
%: C 74.67; H 10.05; N 7.35. C12H19NO. Calculated,
%: C 74.57; H 9.91; N 7.24.
Ritter reaction with 5-hydroxyadamantan-2-one
(III). Compound III, 0.6 g (3.6 mmol), was dissolved
in 1.2 ml of acetonitrile, and 1.2 ml of boron tri-
fluoride–ether complex was added. Trifluoroacetic
acid, 2 ml, was then added dropwise under stirring, and
the mixture was heated for 3 h and was left overnight
at room temperature. The mixture was evaporated
to dryness, the dark oily residue was treated with
a saturated solution of NaHCO3, the products were
extracted into chloroform, and the extract was dried
over Na2SO4, filtered through a layer of silica gel, and
evaporated on a rotary evaporator. The residue was
subjected to column chromatography on Al2O3 using
chloroform as eluent to isolate 0.24 g of compound IV
(Rf 0.41), 0.12 g of V (colorless crystals, Rf 0.1), and
a product with Rf 0.52 (see above).
N-(2-Adamantyl)benzamide (VIb). A mixture of
1 g (6.7 mmol) of adamantan-2-one, 2 ml of benzo-
nitrile, 2 ml of boron trifluoride–ether complex, and
3.2 ml of trifluoroacetic acid was stirred for 3 h on
heating. Excess BF3·Et2O and CF3COOH was distilled
off under reduced pressure, a saturated solution of
sodium hydrogen carbonate and methylene chloride
were added to the residue, and the mixture was
extracted with methylene chloride. The combined
extracts were dried over MgSO4 and filtered through
a layer of silica gel to remove tarry impurities. The
resulting dark solution contained two compounds with
Rf 0.95 and 0.5 (silica gel, CH2Cl2–ethyl acetate, 1:1).
The products were separated by column chromatog-
raphy on silica gel using chloroform as eluent to
isolate benzamide (which was identified by the melting
1
Compound IV. Yield 32%, mp 135–142°C. H
NMR spectrum (CCl4), δ, ppm: 6.0 s (1H, NH), 3.85 s
(1H, adamantane), 1.8–2.7 m (15H, adamantane),
1.93 s (CH3). Mass spectrum: m/z 207 [M]+. Found, %:
C 69.25; H 8.36; N 6.42. C12H17NO2. Calculated, %:
C 69.54; H 8.27; N 6.76.
1
point, H NMR spectrum, and elemental analysis) and
compound VIb (Rf 0.27, chloroform). Compound VIb
was additionally purified by recrystallization from
toluene. Yield 1 g (59%), colorless crystals, mp 167–
1
168°C. H NMR spectrum (CDCl3), δ, ppm: 7.45–
Compound V. Yield 13%, mp 216–218°C
1
7.90 m (5H, Ph), 6.50 br.s (1H, NH), 4.27 m (1H,
NCH), 2.08 br.s (2H, adamantane), 1.95–1.7 m (12H,
adamantane) 1.92 s (CH3). 13C NMR spectrum
(CDCl3), δC, ppm: 167.0 (C=O); 135.5, 131.5, 128.9,
127.1 (Carom); 54.5 (CN); 37.9, 37.75, 31.15, 31.0
(adamantane); 27.6 (CH3). Mass spectrum, m/z: 255
[M]+, 254, 238, 212, 198, 150, 134. Found, %:
C 80.16; H 8.57; N 5.51. C17H21NO. Calculated, %:
C 79.96; H 8.29; N 5.48.
(decomp.). H NMR spectrum (CDCl3), δ, ppm:
5.9 br.s and 5.68 br.s (1H, NH at C4), 5.29 br.s (1H,
NH at C1), 3.05 m (1H, NCH), 1.6–2.2 m (19H,
13
adamantane), 2.01 s and 1.93 s (CH3). C NMR spec-
trum (APT, DMSO-d6), δC, ppm: 169.76 and 169.66
(C=O), 53.28 and 52.69 (1:4, C4), 50.40 (C1), 41.25
(CH2), 40.79 (2CH2), 32.59 (2CH), 30.25 (2CH2), 28.9
(CH), 23.95 (CH3), 22.95 (CH3). Mass spectrum, m/z:
250 [M]+, 235, 207, 191, 176, 148, 132. Found, %:
C 66.91; H 9.27; N 10.92. C14H22N2O2. Calculated, %:
C 67.17; H 8.85; N 11.18.
N-(1-Methyl-4-oxo-2,4-diphenylbutyl)acetamide
(VII). The procedure for the Ritter reaction was the
same as decribed above for compound III. Yield 56%,
mp 105–106°C; published data [12]: mp 93–94°C. IR
spectrum, ν, cm–1: 3300 (NH), 1700 (C=O), 1660
The product with Rf 0.52 was subjected to addi-
tional chromatographic purification on Al2O3 using
CH2Cl2–acetone (4:1) as eluent. Yield 0.04 g (10%).
Found, %: C 69.37; H 8.43; N 6.85. C12H17NO2. Cal-
culated, %: C 69.54; H 8.27; N 6.76.
1
(C=O, amide). H NMR spectrum (CDCl3), δ, ppm:
7.85–7.25 m (10H, Harom), 6.99 br.s (1H, NH), 3.81 d
(1H, J = 17 Hz) and 3.50 d (1H, J = 17 Hz) (diastereo-
topic CH2 protons), 1.95 s (3H, CH3), 1.85 s (3H,
CH3). 13C NMR spectrum (CDCl3), δC, ppm: 199.0
(C=O); 169.0 (C=O, amide); 136.0, 133.4, 128.4,
128.0, 126.5, 124.6 (Carom); 57.0 (CN); 47.5 (CH2);
24.8 (CH3); 25.5 (CH3). Found, %: C 76.84; H 6.92;
N 5.34. C18H19NO2. Calculated, %: C 76.86; H 6.81;
N 4.97.
N-(2-Adamantyl)acetamide (VIa). The procedure
for the Ritter reaction was the same as described above
for compound III. An analytical sample of VIa was
obtained by vacuum sublimation at 170–180°C
(10 mm). Yield 78%, mp 190°C (in a sealed capillary).
1H NMR spectrum (CDCl3), δ, ppm: 5.93 s (1H, NH),
4.05 m (1H, NCH), 1.99 s (3H, CH3), 1.6–1.95 m
(14H, adamantane). 13C NMR spectrum (CDCl3), δC,
ppm: 168.6 (C=O), 53.2 (CN), 37.6 (C6), 37.2 (C8 and
C10), 32.0 (C1, C3, C4, C9), 27.5 (C5, C7), 23.5 (CH3).
Mass spectrum, m/z: 193 [M]+, 178, 150, 134. Found,
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 02-03-32790).
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6. Faulkner, D. and McKervey, M.A., J. Chem. Soc. C,
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